with malignant medullary thyroid carcinoma. 12 The therapy is focused on resection of the primary lesion. We describe a patient who was found to have

Transcription

1 CASE REPORT LARGE CELL CARCINOMA AND VERNER-MORRISON SYNDROME Large Cell Carcinoma With Calcitonin and Vasoactive Intestinal Polypeptide Associated Verner-Morrison Syndrome KEITH W. PRATZ, MD; CYNTHIA MA, MD; MARIE-CHRISTINE AUBRY, MD; TERRI J. VRTISKA, MD; AND CHARLES ERLICHMAN, MD Verner-Morrison syndrome, characterized by diarrhea, hypokalemia, and hypochlorhydria, is caused most commonly by vasoactive intestinal polypeptide secreting islet cell tumors of the pancreas. Verner-Morrison syndrome has not been described as a paraneoplastic syndrome in non small cell lung cancer. We describe a 38-year-old man with metastatic non small cell lung cancer of large cell carcinoma with neuroendocrine differentiation who presented with bone metastasis and intractable secretory diarrhea that was unresponsive to pharmacological treatment, including octreotide. Laboratory evaluation indicated elevated serum calcitonin and vasoactive intestinal polypeptide levels. Chemotherapy resulted in a transient response in the patient s diarrhea and neuroendocrine markers. The patient did not respond to further therapy and died 5 months after onset of back pain. To our knowledge, this is the first published case of large cell carcinoma with neuroendocrine differentiation associated with treatmentresponsive paraneoplastic Verner-Morrison syndrome. Mayo Clin Proc. 2005;80(1): camp = cyclic adenosine monophosphate; CEA = carcinoembryonic antigen; CT = computed tomography; IV = intravenous; LCCND = large cell carcinoma with neuroendocrine differentiation; NSCLC = non small cell lung cancer; PTH = parathyroid hormone; ULN = upper limit of normal; VIP = vasoactive intestinal polypeptide Secretory diarrhea is caused most commonly by infection. 1 Secretory diarrhea is defined by a stool osmotic gap less than 50 mosm/kg. Typically, it is mediated by a cyclic adenosine monophosphate (camp) pathway best described in Vibrio cholerae enterotoxin. This leads to increased secretion of intracellular chloride and bicarbonate and decreased absorption of intraluminal sodium. Patients with enterotoxin-mediated diarrhea present with severe hypokalemia secondary to potassium loss in the stool and dehydration due to concomitant free water loss. Evaluating a patient who presents with chronic secretory diarrhea can be complicated. Patients may present with large volumes of watery diarrhea refractory to traditional From the Department of Internal Medicine (K.W.P.), Department of Internal Medicine and Division of Hematology (C.M.), Department of Laboratory Medicine and Pathology and Division of Anatomic Pathology (M.-C.A.), Department of Radiology and Division of Computed Tomography (T.J.V.), and Department of Oncology and Division of Medical Oncology (C.E.), Mayo Clinic College of Medicine, Rochester, Minn. Individual reprints of this article are not available. Address correspondence to Keith W. Pratz, MD, Department of Internal Medicine, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN ( Mayo Foundation for Medical Education and Research antidiarrheals such as atropine or loperamide. Patients often undergo a gastrointestinal evaluation, including multiple stool studies for infection, laxative abuse, protein-losing enteropathy, and inflammatory bowel disease. Also, patients often undergo upper and lower endoscopies to exclude underlying colitis, celiac sprue, vasculitis, intestinal lymphangiectasia, and lymphoma. In most cases, these investigations are sufficient for finding the etiology of the diarrhea. However, if no source is found, an endocrine cause must be considered for this extremely debilitating problem. In secretory diarrhea induced by paracrine hormones such as vasoactive intestinal polypeptide (VIP), calcitonin, and gastrin, the stimulus for chloride secretion is via the same camp mechanism as Vibrio toxin. A VIPoma syndrome, originally described in the Verner-Morrison syndrome, 2 has been referred to as pancreatic cholera or endocrine cholera because the stool resembles that of patients with cholera. This syndrome has been associated with islet tumors of the pancreas, neuroblastomas, ganglioneuroblastomas, and ganglioneuromas. Patients with VIPomas often have profound hypercalcemia and non anion gap metabolic acidosis. Another effect specific to the hormone is hypokalemia from VIP-induced hyperaldosteronism. 3 Such patients require aggressive hydration and supplementation of potassium to correct ongoing loss. The current suggested management for VIP-induced diarrhea is with somatostatin analogues such as octreotide. 4 The response rate (improvement of diarrhea) varies but has been reported to range from 90% to 95%, with complete response between 10% and 65%. 5,6 Less is known about calcitoninsecreting tumors associated with diarrhea. Like VIP, calcitonin can cause profuse secretory diarrhea, hypokalemia, and dehydration. 7 Most cases are associated with pancreatic islet cell tumors 7 or medullary thyroid carcinoma, 8 with scattered case reports of pulmonary carcinoid tumors secreting calcitonin. 9 In addition, calcitonin has been documented by radio-labeled immunoassay to be ectopically produced by small cell lung cancer. 10 Infusions of synthetic salmon calcitonin have been shown to increase jejunal secretion in 8 of 10 healthy volunteers, 11 suggesting a possible etiology of diarrhea associated with medullary thyroid carcinoma. Unlike for VIPomas, published reports do not support the use of somatostatin-related compounds in the treatment of calcitonin-induced diarrhea associated 116

2 with malignant medullary thyroid carcinoma. 12 The therapy is focused on resection of the primary lesion. We describe a patient who was found to have non small cell lung cancer (NSCLC), classified as large cell carcinoma with neuroendocrine differentiation (LCCND), with elevated levels of serum calcitonin and VIP. Our treatment with somatostatin analogues, antidiarrheals, and chemotherapy with etoposide and cisplatin did not halt progression of disease but temporarily improved diarrheal symptoms and ectopic hormone levels. REPORT OF A CASE A 38-year-old man presented to the medical oncology department at the Mayo Clinic in Rochester, Minn, after 2 months of progressive mid-thoracic back pain. Subsequently, the patient required narcotic analgesics for relief of pain and developed a right foot drop. Magnetic resonance imaging of the thoracic spine revealed a compression fracture of the T7 vertebra with impingement on the adjacent spinal cord. The patient was given intravenous (IV) corticosteroids for spinal cord compression and underwent vertebrectomy of the T7 vertebra 2 days later. The pathology of the vertebral specimen was reported as a malignant neoplasm not further classifiable due to widespread necrosis, and ancillary studies with an extensive panel of immunohistochemical stains were noncontributory. The patient was noted to have a normal complete blood cell count and electrolyte panel; also, computed tomographic (CT) scans of the chest, abdomen, and pelvis were normal. Subsequent laboratory test results included normal serum protein electrophoresis, an elevated serum carcinoembryonic antigen (CEA) of 39.5 ng/ml (upper limit of normal [ULN], 3.0 ng/ml), and normal levels of alpha fetoprotein and β-human chorionic gonadotropin. The patient was otherwise asymptomatic and was observed for 2 weeks. Five weeks after surgery, the patient developed profuse watery diarrhea, initially believed to be related to postoperative antibiotics. However, no stool analyses were performed at that time. Approximately 6 to 7 weeks after the patient s spinal surgery, he presented to the Mayo Clinic for evaluation of malignancy of unknown origin, persistent back pain, and uncontrollable diarrhea. Initial blood test results revealed the following (reference ranges shown parenthetically): sodium, 137 meq/l ( meq/l); potassium, 2.8 meq/l ( meq/l); calcium, 14.4 mg/ dl ( mg/dl); CEA, ng/ml ( 3.0 ng/ml); alkaline phosphatase, 440 U/L ( U/L); prostatespecific antigen, 5.0 ng/ml (<2.0 ng/ml); lactate dehydrogenase, 304 U/L ( U/L); aspartate aminotransferase, 57 U/L (12-31 U/L); and bicarbonate, 20 meq/l (22-29 FIGURE 1. Chest x-ray film on admission shows normal findings except for postoperative changes of the vertebrectomy. meq/l). Test results for magnesium, glucose, total bilirubin, direct bilirubin, creatinine, and serum urea nitrogen were normal. The patient was admitted to the hospital for treatment of hypercalcemia and dehydration. On admission, the patient s physical examination revealed a moderately wasted man. No skin changes were noted. Examination of his chest, heart, and extremities revealed only tachycardia. The patient had no palpable lymph nodes or thyroid nodules. Abdominal examination was notable for hyperactive bowel sounds, mild distention, no organomegaly, and mild tenderness of the left lower quadrant. Chest radiographic findings were normal except for postoperative changes of the vertebrectomy (Figure 1). The patient was treated with fluid hydration and 4 mg of IV zoledronic acid for hypercalcemia of malignancy. The hypercalcemia improved within 3 days of treatment. With hydration, the patient s potassium level decreased to 2.1 meq/l on day 5 of hospitalization. Continuous IV infusion of potassium chloride at 10 meq/h and oral potassium chloride at 40 meq every 8 hours did not improve his hypokalemia. His diarrhea worsened to approximately 5 L of stool per day. The patient s stool osmolality was 299 mosm/kg ( mosm/kg). Stool electrolytes were as follows: sodium, 7 meq/kg (ULN, 160 meq/kg); potassium, 157 meq/kg (ULN, 200 meq/kg); chloride, 42 meq/kg (ULN, 40 meq/kg); magnesium, 2 meq/kg (ULN, 200 meq/kg). The patient s stool osmotic gap was calculated at 38 mosm/kg, consistent with a secretory 117

3 FIGURE 2. Chest computed tomogram shows nodules in 2 slices of the right upper lung. diarrhea. Bacterial cultures (number of cultures in brackets) were negative (including Aeromonas [2], Clostridium difficile toxin screens [6], ova and parasite screens [2], Giardia antigen [2], and Cryptosporidia, Isospora, and Microsporidia [1 each]). Esophagogastroduodenoscopy with small bowel biopsies revealed normal mucosa with no evidence of Whipple disease, celiac sprue, or Giardia. Colonoscopy showed normal colonic mucosa with no evidence of microscopic colitis or inflammatory bowel disease. The patient was given a maximal dose of loperamide and atropine/diphenoxylate without improvement in symptoms. Subcutaneous octreotide, up to 300 µg 4 times a day, was added with no quantitative or symptomatic relief in high-volume diarrhea. Also, tincture of opium was added without success. On hospital day 2, CT of the chest, abdomen, and pelvis was repeated to look for the primary source of malignancy. Computed tomography (Figure 2) revealed diffuse small lytic lesions throughout the visualized skeleton, the largest of which was 5 mm. Moderate lymphadenopathy was noted in the right paratracheal space with 2 noncalcified indeterminate nodules in the apex of the right lung, the largest being 1 cm. Multiple small metastatic lesions were present throughout the liver and kidneys, the largest being 6 mm. Mediastinoscopy with lymph node biopsy was performed. The histological features were those of a large cell carcinoma of lung origin, confirmed by positive immunoreactivity for keratin, CAM 5.2, and thyroid transcription factor 1 tumor markers (Figure 3, left). Neuroendocrine differentiation was confirmed at an immunohistochemical level with positive immunoreactivity for chromogranin (Figure 3, right); however, the neoplastic cells were negative for calcitonin and VIP. The patient s serum was screened for paraneoplastic causes of diarrhea. His VIP level was elevated at 2200 pg/ ml (ULN, 75 pg/ml); calcitonin level was elevated at 9571 pg/ml (ULN, 15.9 pg/ml); corticotropin level was elevated slightly at 82 pg/ml (ULN, 60 pg/ml); and gastrin level was normal. The patient s thyrotropin level was depressed at 0.26 miu/l (lower limit of normal, 0.30 miu/ L), but both total and free triiodothyronine levels were within normal limits. The parathyroid hormone (PTH) related peptide level was normal, and the PTH level was elevated at 24 pmol/l (ULN, 5.2 pmol/l). The patient was given etoposide and cisplatin chemotherapy for NSCLC. The patient responded clinically within 2 days of treatment with substantial improvement in stool volume of less than 1 L per day. Next, parenteral potassium chloride was gradually decreased and discontinued. The patient s potassium level stabilized at 3.8 meq/l. Serum markers for disease improved with treatment (Figure 4). Four days after treatment, the patient s calcitonin level decreased from 9571 to 3738 pg/ml, and his VIP level decreased from 2200 pg/ml to 428 pg/ml. However, his CEA level increased from 161 ng/ml to 299 ng/ml. The patient s improvement was transient. He returned home, but within 2 weeks of treatment, his diarrhea and associated hypokalemia returned. A repeated calcitonin test revealed that the level had increased to 10,000 pg/ml or higher. The patient received a repeated course of etoposide and cisplatin, which improved both his diarrhea and potassium level for 1 week. Repeated CT of the abdomen showed enlarging liver metastases. Chemotherapy was changed to docetaxel and carboplatin without benefit. Shortly thereafter, the patient developed Candida sepsis and died. DISCUSSION To our knowledge, this is the first published case of a paraneoplastic syndrome characterized by secretory diarrhea due to the secretion of multiple active hormones, VIP and calcitonin, by metastatic pulmonary LCCND. Endocrine paraneoplastic syndromes occur in approximately 20% of patients with lung cancer but are associated much more commonly with small cell lung cancer and carcinoid tumors because of their neuroendocrine differentiation, 118

4 FIGURE 3. Left, Intermediate-power photomicrograph of malignant neoplasm within paratracheal lymph node shows lack of glandular or squamous differentiation. The cells are large and pleomorphic with areas of necrosis (hematoxylin-eosin, original magnification 100). Right, Neoplastic cells, diffusely positive for chromogranin, show neuroendocrine differentiation by immunohistochemistry (chromogranin, original magnification 100). which is characterized ultrastructurally by the presence of neuroendocrine granules and by immunoreactivity with different neuroendocrine markers, including chromogranin and synaptophysin. However, up to 20% of NSCLC, including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, can display similar neuroendocrine differentiation and thus may explain the occurrence of endocrine syndromes with these subtypes, as seen in our patient. A common neuroendocrine syndrome described with NSCLC is hypercalcemia of malignancy, secondary to osteolytic bone metastases and ectopic production of PTH or PTH-related peptide. Multiple other neuroendocrine syndromes have been described. Most are case reports, with large cell carcinoma described in association with ectopic secretion of chorionic gonadotropin, growth hormone, glucagon, and gastrin, but not with VIP. Although secretion of calcitonin has been described in NSCLC including large cell carcinoma, it usually has not been associated with any clinical manifestation. Seven described neuroendocrine tumors can cause diarrhea: gastrinomas (Zollinger-Ellison syndrome), VIPomas (Verner-Morrison syndrome), glucagonomas, somatostatinomas, pancreatic endocrine tumors secreting calcitonin, medullary thyroid cancer, and carcinoid syndrome. 4 These constitute a rare form of chronic diarrhea but should be considered when all other causes have been ruled out. Helpful features in identifying a paraneoplastic endocrine syndrome as the cause of chronic diarrhea include identification of a malignancy and the development of hypokalemia and hypercalcemia in association with fasting hyperglycemia. Verner-Morrison syndrome is most commonly caused by islet cell tumors of the pancreas secreting VIP, but calcitonin has been noted as a possible cause in some patients. 13 Interestingly, immunohistochemical studies of our patient s tumor revealed no calcitonin or VIP in the tumor. This suggests rapid release of synthesized hormone, reaching high levels in the blood and low to absent levels in tumor cells, similar to pancreatic epithelial VIPoma. 14 Alternatively, the tumor conceivably produced another as-yet unidentified substance that stimulated abnormal production of VIP and calcitonin by normal tissues. Elevation of calcitonin levels has been described in other forms of lung pg/ml 10, Hospital day FIGURE 4. Endocrine tumor markers. Initiation of chemotherapy was on hospital day 11. We observed a substantial decline in tumor marker levels within 3 days. VIP = vasoactive intestinal polypeptide. 119

5 injury such as pneumonia, tuberculosis, and chronic obstructive pulmonary disease, 15 but not at levels causing paraneoplastic symptoms. Treatment resulted initially in a good biochemical response in VIP and calcitonin levels, but the CEA level increased soon after initiation of treatment. This response has been reported immediately after chemotherapy for colorectal cancer, 16 breast cancer, 17 and non seminoma germ cell tumor 18 despite objective tumor response. An LCCND is generally a high-grade tumor with a poor prognosis. 19 Large cell carcinoma with neuroendocrine differentiation belongs to a group of poorly differentiated NSCLCs that can be divided into tumors that have neuroendocrine features on light microscopy and those that have only evidence of neuroendocrine differentiation detected on immunohistochemical staining (ie, synaptophysin, chromogranin, and neuron-specific enolase). The importance of neuroendocrine differentiation as a prognostic marker and as a marker of response to chemotherapy is controversial, with studies indicating better 20,21 or worse survival or response 22 or no difference 23 in survival or response to chemotherapy at all stages. The aggressive nature of the tumor and the stress on the patient caused by Verner-Morrison syndrome presented a dilemma for the medical team. The use of chemotherapy when the primary source of the malignancy was unclear and the tumor type was poorly defined was complicated by the concern that many chemotherapies are associated with diarrhea as a common adverse effect. Nevertheless, when the paraneoplastic mechanism for the secretory diarrhea was determined, it required specific treatment of the tumor to control the symptoms because all other supportive measures had failed. Although the benefit of chemotherapy was shortlived, it allowed the patient to return home to spend valuable time with his family. 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